Every pH electrode is an imperfect tool that functions unevenly over the whole pH range, and every pH reading involves a possibly variable liquid junction potential. Accordingly, it is necessary to have a standard or reference solution against which one can confirm the accuracy of a pH measurement system.
The National Bureau of Standards has identified a series of aqueous buffers that are commonly used to create solutions of specific pH values at specific temperatures. Weast, R. ed., CRC Handbook of Chemistry and Physics, (1979), p. D147-D149. The pH of the standards is temperature dependent, primarily because of the variation of the Ka of the buffer system with temperature. The buffers comprise various active ingredients, e.g. phosphate, phthalate, borax, tartrate, etc. For measurements near neutral pH levels (6-8), the industry standard for pH electrode calibration solutions is a phosphate buffer.
Occasionally, however, pH measurements must be made in vivo, or in physiological environments or materials that must be isolated or protected from microorganisms and associated antigenic substances such as pyrogens. In such instances, additives such as biocides are introduced to inhibit microbial growth during processing, and a sterilization cycle is performed to ensure sterility of the finished formulation. Both measures can affect the pH of the standard solution.
The addition of preservatives such as biocides alters the physicochemical properties of the formulation and increases the potential for chemical interactions. Among other things, those new properties and interactions can alter the pH, and thereby render the solution ineffective for its intended purpose.
Likewise, the introduction of a sterilization cycle to ensure the sterility of the finished formulation can complicate the physicochemical profile of the sterilized product. Further, sterilization complicates the selection of a preservative since any such preservative must first be an effective biocide, but must also withstand the rigors of sterilization without affecting the pH, stability, cosmetics, or biocompatibility of the buffer. The preservative does not need to retain biocide effectivity post-sterilization, as long as it does not otherwise adversely affect the performance of the product.
Phosphate buffered solutions are preferred calibration buffers for neutral pH. However, phosphate buffers are excellent growth media for microorganisms. Even short periods between buffer manufacture and product sterilization can lead to bioburden levels high enough to threaten the integrity of a sterilization cycle. Conventional calibration buffers used for common laboratory pH electrodes often do not use preservatives. This is because the end application of such buffers is concerned solely with pH, and is not concerned with bioburden (which generally does not affect the pH of those well-buffered solutions). Medical device manufacturers, however, do not have this luxury. Systems and solutions used for the measurement of pH must often be aseptic. Thus, there is a need within the art for buffer formulations for pH measurement containing adequate biocide to inhibit microbial growth, while also being capable of withstanding the rigors of sterilization without affecting pH.